European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), The Genome Campus, Hinxton, Cambridge, CB10 1SD, UK.
Department of Genetics, Evolution and Environment, Institute of Healthy Ageing, University College London, Gower Street, London, WC1E 6BT, UK.
Aging Cell. 2017 Oct;16(5):1006-1015. doi: 10.1111/acel.12626. Epub 2017 Jun 16.
Many increasingly prevalent diseases share a common risk factor: age. However, little is known about pharmaceutical interventions against aging, despite many genes and pathways shown to be important in the aging process and numerous studies demonstrating that genetic interventions can lead to a healthier aging phenotype. An important challenge is to assess the potential to repurpose existing drugs for initial testing on model organisms, where such experiments are possible. To this end, we present a new approach to rank drug-like compounds with known mammalian targets according to their likelihood to modulate aging in the invertebrates Caenorhabditis elegans and Drosophila. Our approach combines information on genetic effects on aging, orthology relationships and sequence conservation, 3D protein structures, drug binding and bioavailability. Overall, we rank 743 different drug-like compounds for their likelihood to modulate aging. We provide various lines of evidence for the successful enrichment of our ranking for compounds modulating aging, despite sparse public data suitable for validation. The top ranked compounds are thus prime candidates for in vivo testing of their effects on lifespan in C. elegans or Drosophila. As such, these compounds are promising as research tools and ultimately a step towards identifying drugs for a healthier human aging.
年龄。然而，尽管许多基因和途径被证明在衰老过程中很重要，而且许多研究表明遗传干预可以导致更健康的衰老表型，但针对衰老的药物干预措施却知之甚少。一个重要的挑战是评估将现有药物重新用于模型生物初步测试的潜力，在这些实验中是可能的。为此，我们提出了一种新方法，根据已知哺乳动物靶点的药物样化合物在秀丽隐杆线虫和果蝇中调节衰老的可能性对其进行排序。我们的方法结合了关于衰老的遗传效应、同源关系和序列保守性、3D 蛋白质结构、药物结合和生物利用度的信息。总的来说，我们根据药物样化合物调节衰老的可能性对 743 种不同的化合物进行了排序。尽管可用的验证性公共数据稀疏，但我们的排名成功地富集了许多用于调节衰老的化合物的证据。因此，排名靠前的化合物是在秀丽隐杆线虫或果蝇中测试其对寿命影响的体内试验的首选候选物。因此，这些化合物作为研究工具很有前景，最终可能会发现有助于人类健康衰老的药物。
